Microlayer coextrusion to create a time-release drug substance delivery product

ABSTRACT

The present disclosure relates to medical devices containing time-release drug substance, and more particularly, to medical tubing, catheters, stents, cables (including fiber optic cables), pills, capsules, sheaths, threads, clamps, sutures, and endotracheal devices. The invention also generally relates to a method for extruding multiple laminated flow streams using microlayer coextrusion to create these various time-release drug delivery products.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/748,542filed on 23 Jan. 2013 which is a continuation-in-part of U.S.application Ser. No. 13/681,413, filed on 19 Nov. 2012, which itselfclaims priority to and the benefit of U.S. Provisional Application Ser.No. 61/561,165, filed on 17 Nov. 2011, and is a continuation-in-part ofU.S. application Ser. No. 13/336,825, that issued as U.S. Pat. No.9,381,712, which itself claims priority to and the benefit of U.S.Provisional Application Ser. No. 61/460,042, filed 23 Dec. 2010, thedisclosures of which are incorporated herein by reference in theirentireties.

FIELD

The present disclosure relates to medical devices containingtime-release drug substance, and more particularly, to medical tubing,catheters, stents, cables (including fiber optic cables), pills,capsules, sheaths, implants, threads, clamps, sutures, tapes, sheets andendotracheal devices. The present disclosure also generally relates to amethod for extruding multiple laminated flow streams using microlayercoextrusion to create these various time-release drug delivery products.

BACKGROUND

The use of polymers in biomedical applications has been on a rise sincethey were first introduced in this field. This has been possible due tothe unique combination of properties exhibited by polymers such asflexibility, ease of processing and excellent biocompatibility.Biopolymers are being used in many medical devices involving life savingapplications. Artificial implants, drug delivery systems, lubriciouscoatings for less invasive devices, biological adhesives,anti-thrombogenic coatings and soft tissue replacements are a few of thecurrent commercial applications. Researchers around the world are tryingto improve these materials to make them more versatile in theirapplications with an aim to eliminate the current problems associatedwith them.

SUMMARY

The present invention relates to an extruded medical device capable ofdelivering an agent in a time dependent fashion. In a microlayerextrusion process, each of a laminated flow stream(s) (containing thedesired agent(s)) is subject to repeated steps in which the flows aredivided and overlapped to amplify the number of laminations. Theamplified laminated flows are rejoined to form a cumulated laminatedoutput which may achieve dimensions as thin as the micro or nanometerrange.

These sustained release drug emitting medical devices achieve microlayerand polymeric geometries with enhanced delivery properties.

The present invention relates to an extruded medical device comprisingone or more pharmaceutical product(s) or drug substances (includingmixtures thereof) layered with one or more biocompatible materials thatcontrol the time release of the delivery of the drug substance.

Medical devices include catheters, stents, threads, cables (includingfiber optic cables), pills, capsules, lozenges, tablets, implants,medical tubing, sheaths, clamps, sutures, tapes, sheets and endotrachealdevices.

An embodiment of the invention relates to a medical tubular devicecomprising: a polymeric tube containing small sized grains, nano ormicro-sized features and a drug substance.

Another embodiment relates to a medical tubular device comprisingmulti-lumen tubes. Another more specific embodiment relates to a medicaltubular device comprising two to five multi-lumen tubes in combinationwith one or more annular tubes.

Another embodiment relates to a medical annular device comprising:polymeric layers containing small sized grain, nano or micro-sizedfeatures and a drug substance.

Another embodiment relates to a medical tubular device with a foldedannular cross-section as described herein wherein said medical device isa stent. Another embodiment of said stent contains nano or micro-sizedfeatures formed into folds or skin layers. Another embodiment of saidstent containing nano or micro-sized features is formed into folds orskin layers that have separated at the fold interface.

Another embodiment relates to a medical tubular device comprising: amulti-component polymeric tube containing an embedded/extruded annularstem of a first polymer and a support surface surrounding saidembedded/extruded stem containing a second polymer wherein each of saidfirst and second polymer may contain one or more drug substances.

Another embodiment relates to a medical tubular device as describedabove wherein said medical tubular device is an orally administrablemedicament such as a pill or capsule.

Another embodiment relates to a medical annular device as describedherein wherein said medical annular device is an orally administrablemedicament such as a pill or capsule.

Said medical annular device is a polymer solid comprising from two tothousands of annular layers. Any of the extruded geometries mentionedherein (such as annular, core, stem or folded) may be used to createpills or tablets. The different layers can contain different polymerseach of which may or may not contain a drug, which is not necessarilythe same for each layer.

Another embodiment relates to a medical device comprising a polymersolid of micro or nano sized annular rings, optionally emanating fromthe center of a drug substance core.

Another embodiment relates to a medical device as described abovewherein said device is a pill or capsule comprising a polymer solid ofannular rings.

Another embodiment relates to a medical device comprising a polymersolid of annular rings containing a drug substance emanating from acenter inactive core.

Another embodiment relates to an implantable drug delivery systempossessing electronic conduction properties so as to actuate a targettissue or sense a parameter associated with the target tissue. One morespecific aspect of the present disclosure relates to taking anon-conductive material, such as a polymer, and creating an electricallyconductive product in the nano-flow die using the polymer.

In another embodiment, making an electrically conductive productcomprises filling the polymer with metal. The term “filling” isgenerally used to define a state where there are sufficient conductiveparticles within the product to establish a conductive state. As willgenerally be understood in the art, this can include a product layerthat only partially comprises conductive elements or particles. Inalternate embodiments, any suitable material that enables or providesfor electrical conductivity can be used to create an electricallyconductive product using the polymer, including metals.

Another embodiment relates to an implantable drug delivery systemsincluding Reservoirs, Matrix or Osmotic pumps. For these devices, theextruded flow includes the core and stem cross sectional geometriesdescribed herein. The center area of these flows may be a drug reservoircomprising a non degradable matrix containing a drug substance or abiodegradable drug substance matrix. The outer rings may be permeablenondegradable membrane, biodegradable polymer membrane, or additionalpolymer layers containing drug substance or a different drug substancewhere dissolution of polymer controls drug release.

Another embodiment relates to an implantable drug delivery system whichis an osmotic pump comprising a tubular stem cross sectional geometryflow comprising an osmotic center area of said flow and one or moreouter rings comprising permeable or semipermiable nondegradablemembranes.

In a reservoir drug delivery system, a concentrated drug substance coreis surrounded by a permeable membrane. This membrane may be comprised ofnondegradable or biodegradable polymers. The diffusivity of the membranemay be tailored using microlayer coextrusion. The annular rings createdby the micro- or nanolayer die form a membrane composed of multiplepolymer layers where the diffusivity is determined by the polymers usedand also the layer properties created through microextrusion. In abiodegradable membrane the erosion of the membrane may also becontrolled through the microlayered annular rings. In typicalbiodegradable systems, as the polymer degrades the surface area of thedrug substance increases. This may lead to a varying drug release rate.With a microlayered time-release drug substance the thickness andconcentration may be altered to achieve a more uniform and constantrelease. Drug substance microparticles (and/or nano particles) may alsobe added to individual or multiple layers. As the layers biodegrade,these drug substance particles would be released.

In another embodiment, the cumulated laminated output may compriselayers solely of drug substances. Additionally, each layer may contain adifferent drug substance or a different concentration or form thereof.The layers may be alternated in any suitable fashion. When the cumulatedlaminated output includes time-release components or layers, as eachtime-release layer is dissolved by the body, a layer of drug substancewould be administered in a manner generally understood in the art.

Layers or layered as used herein refers to flow streams as well as thelaminated output and annular geometries. Such output and geometries mayhave small sized grain features, generally in the range of micro andnanosized grain features. Integrated laminated streams may also havesmall size grain features and helical grain orientation. Layers alsoform as an embodiment of flow streams in the form of laminated ribbonsand retain a layered structure corresponding to the number oflaminations. Gradually thinner laminations may be formed within theextrusion flow, thereby obtaining smaller and smaller grain features andeventually obtaining micro or nano-sized features. The flows possessdistinct boundary features.

Layers also refers to annular cross-sections of flow streams and medicaldevices, such as circular, elliptical, or oval shapes. Additionally, anyof the extruded annular geometries mentioned herein (such as annularrings, core, stem or folded) may be used for pills or tablets. Extrudedannular geometries mentioned herein (such as annular rings, core, stemor folded) may be used for implants, threads, sutures. catheters(wherein the core is hollow or a solid rod, a hollow tube, a wire, or aprofile all of which may either be coextruded or extruded onto and maybe comprised of any materials with or without layers. The core may alsobe absent.) Such geometries comprise two to thousands of such layers.The different layers can contain different polymers each of which may ormay not contain a drug, which is not necessarily the same for eachlayer.

Some of the aspects of the disclosed embodiments are directed to formingthe layers resulting in the cumulated laminated output by a microlayercoextrusion die. The microlayer coextrusion die may form the layers inannular rings that emanate from the center of the drug substancedelivery device. The layers that form the drug substance containingdevice may be concentric. The drug substance containing polymer may beextruded in various cross-sections, such as circular, elliptical, oroval shapes. The thickness of each layer may also vary depending uponone or more factors such as the desired time release or the requireddosage of the drug. The nanolayer die may be used to make the product,except that in this situation the center is not hollow.

Another embodiment of the invention relates to the time releasecharacteristics of the produced drug delivery device may be controlledthrough the barrier properties of annular rings. Small micro- ornano-sized layers may induce confined polymer crystallization. Theseconfined crystals may result in unique barrier properties. Polymernanocomposities may also be used to control the properties of the drugsubstance. Particles added to the polymer may alter the diffusivity ofthe polymer surface or change crystal orientation. These particles mayalso affect barrier properties by providing a tortuous path for apermeate to travel. Permeation though the multilayer structure may beenhanced or impeded through layer size or the introduction of particlesincluding nanoparticles.

Biocompatible materials include polymers such as polyamides, polyimides,polyureas and poly(urethane-urea)s, MPC polymer, polyesters, polyethers,etc. Polyamides such as Polyether Block Copolyamides (PEBA), medicalgrade polyamide 11, and MED polyamide are particularly useful polymers.Other commercially available biocompatible materials include polyvinylpyrrolidone (PVP), Polyethylene oxide (PEO), SoluPlus™, Polyvinylalcohol (PVA), Hydroxypropyl Cellulose (HPC),Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS), Ethylene VinylAcetate (EVA), Methacrylates (Eudragit™), Ethyl cellulose (EC),Cellulose acetate butyrate (CAB), Cellulose Acetate Phthalate (CAP),Poly(ethylene glycol), Poly(vinyl acetate) (PVAc), Polylactide (PLA),Polyglycolide (PGA), copolymers of PLA/PGA, Polycaprolactone (PCL),Polyvinylpyrrolidone-co-vinyl acetate (Kollidon VA-64), andPolyrethanes. Nanocellulose fibers are additional biocompatiblematerials. Bacterial nanocellulose (BNC) is one specific nanocellulosicmaterial embodiment. Other biocompatible materials are described in M.A. Longer and J. R. Robinson, “Sustained-release drug delivery systems,”in Remington's Pharmaceutical Sciences, J. P. Remington, Ed., pp.1676-1693, Mack Publishing, Easton, Pa., USA, 18th edition, 1990.

Another embodiment of the invention relates to the pharmaceuticalproduct(s) or drug substances (including mixtures thereof).

In one more specific embodiment, each layer of the medical device may becomprised of one or more pharmaceutical product(s) or drug substances(including mixtures thereof) alternating with one or more materials thatcontrol the time release of the delivery of the drug substance.

The pharmaceutical products or drug substances include activepharmaceutical ingredients (API) which are dispersed and or dissolvedinto a polymeric matrix flow stream. The extrudate may contain amorphoussolid solutions or dispersion formations. Although the aspects of thepresent disclosure are generally directed to drug delivery, the aspectsof the disclosed embodiments are not so limited and may include anyproduct, composition or substance, for which time release properties aredesirable. These may include for example, but are not limited to,vitamins, medicaments, active and non-active ingredients.

Suitable pharmaceutical agents include antibiotics, angiogenics (such asFibroblast growth factor (FGF), VEGF, and angiopoietins such as Ang1 andAng2), anti-angiogentics (such as bevacizumab, thalidomide,itraconazole, carboxyamidotriazoles, angiostatin, endostatin, linomide),immunomodulators (such as immunophilins ciclosporins, rapamycins,sirolimus, zotarolimus, everolimus, glucocorticoids, cytostatics such asalkylating agents, antimetabolites), anti-inflammatories (such assalicylates, COX-2 inhibitors, propionic acid derivatives, acetic acidderivatives, enolic acid (oxicam) derivatives, fenamic acid derivatives(fenamates) and sulphonanilides), antithrombotics (such as warfarins,heparins and Factor Xa inhibitors), platelet aggregation inhibitors(such as ticlopidine or clopidogrel), antiproliferatives (such asPaclitaxel).

Other agents include neuropharmaceuticals such as antiepileptics,antipsychotics, anti-schizophrenics, and antiparkinsonian agents.

Pain medications are particularly well suited to the aforesaid methodsdue to the abuse remediation potential and the ability to localize thesource of the active agent.

Agents useful in endocrine disorders such as hypoglycemic, insulins,glitzazones etc are also particularly amenable to the present methods.Other such endocrine related agents include parathyroid hormone, vitaminD and calcitonin.

Ophthalmic implants are also envisioned, including 2-methoxyestradiol;angiogenesis compounds such as VEGF antagonists; or corticosteroids. Seefor example U.S. Pat. No. 6,713,081 issued Mar. 30, 2004.

Suitable devices include a drug substance that elutes in a timedependent fashion. For example, concentrations of between 1-99 percentdry weight of the API are contemplated, more particularly 35-80 percentdry weight. Specific concentrations may be tailored to the specificpharmacologic effect desired. Such devices may also elute the drugsubstance for extended periods. For example some products may elute drugsubstance for up to 30-60 days. Other products can be designed to eluteover periods of years subject only to the shelf life of the drugsubstance.

Another embodiment relates to pharmaceutical product(s) which areimplantable devices. Implantable devices include cardiovascular relateddevices such as implantable pacemakers, implantable defibrillators,prosthetic heart valves, ventricular bypass (assist) devices includingLeft Ventricular Assist Device (LVAD), intraaortic balloon pumps,percutaneous catheters, vascular graft prostheses, catheter guidewires,vascular clamps, Pacemakers, and Implantable Cardioverter Defibrillators(ICDs),

Diabetes related devices includes continuous glucose monitoring systemsincluding continuous subcutaneous insulin infusion (CSII) systems,insulin delivery systems such as the Insulet OmniPod® insulin managementsystems, Infusaid, Artificial Pancreas Device Systems (APDS),Implantable Infusion Pumps such as Medtronic's SynchroMed II andSynchroMed EL.

Anesthesiology devices include oropharyngeal airways devices(endotracheal tubes), arterial blood gas sampling devices, esophagealstethoscopes, tracheobronchial suction catheters, carbon dioxide gasanalyzers, and indwelling blood oxygen partial pressure analyzers.

Auditory and balance devices include hearing aids, otoscopes,nasopharyngeal catheters, tympanostomy tubes, bronchoscopes, suctionantichoke devices, cochlear Implants.

Gastrointestinal devices include enema kits, ostomy pouches, endoscopes,lithotriptors, urologic catheters, peritoneal dialysis systems,gastrointestinal tubes (such as nasogastric tubes and feeding tubes),inflatable penile implants, implanted blood access devices (vascularshunts for hemodialysis), and urogynecologic Surgical Mesh Implants.

Other devices include implantable staples, absorbable sutures, surgicaldrapes, surgical clips, skin adhesive, surgical mesh, facial plasticsurgery prostheses (eg, nose, ear, chin), extremity splints, GastricBanding Devices, absorbable hemostatic agents, tissue adhesives, breastimplants and Hernia Surgical Mesh Implants, electroencephalographelectrodes, esthesiometers, ventricular cannulas (needles), intracranialpressure monitor devices, evoked response electrical stimulators,ventricular catheters, aneurysm clip appliers, aneurysm clips, centralnervous system fluid shunts, neuromuscular stimulators, and implantedperipheral nerve stimulators, intravascular occluding catheters, cranialelectrotherapy stimulators, implanted cerebellar stimulators, implanteddiaphragmatic/phrenic nerve stimulators, implanted neuromuscularstimulators, electroconvulsive therapy devices, fetal scalp spiralelectrodes, fetal vacuum extractors, forceps, contraceptive diaphragms,fetal scalp clip electrodes, expandable cervical dilators, andcontraceptive intrauterine devices, prosthetic and surgical devices,such as many manual surgical instruments and many arthroscopic surgicalinstruments including arthroscopes, intramedullary fixation rods, bonecement, and certain portions of joint prostheses.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 illustrates a cross section of one embodiment of an annular layerdrug substance made using the nanolayer die.

FIG. 2 illustrates one embodiment of a product created by the nano die.

FIG. 3 illustrates another embodiment of a product created by the nanodie.

FIG. 4 illustrates another embodiment of a product created by the nanodie.

FIG. 5 illustrates a further embodiment of a product created by the nanodie.

FIG. 6 illustrates a typical flow channel for a product created by thenano die.

FIGS. 7a-c illustrate examples of fold structures using a layer foldingtechnique.

DETAILED DESCRIPTION

General principles regarding the methods and the extrusion die may befound in United States Patent Publication No. 2012/0189789 “Method andApparatus for Forming High Strength Products” and in U.S. Pat. No.7,690,908 issued Apr. 6, 2010. Other methods are described in U.S. Pat.Nos. 6,669,458, 6,533,565 and 6,945,764. Each of the aforesaidpublication or patent is herein incorporated by reference in itsentirety.

General methods for the preparation of drug substance containing flowsis known in the art. See for example Drug Dev Ind Pharm., 2005 May 31(4-5):339-47; U.S. Pat. No. 6,488,963 to McGinity issued Dec. 3, 2002;United States Patent Publication 2011/0229526 published Sep. 22, 2011;U.S. Pat. No. 8,323,760 issued Dec. 4, 2012; and U.S. Pat. No. 8,221,778issued Jul. 17, 2012.

General methods for further processing the cumulated laminated outputinto the particular sustained delivery product are well known in theart. See for example European Journal of Pharmaceutics andBiopharmaceutics, Volume 54, Issue 2, September 2002, Pages 107-117;Breitenbach J., et al., “Two Concepts, One Technology:Controlled-Release Solid Dispersions Using Melt Extrusion (Meltrex),”Drugs and the Pharmaceutical Sciences, 2008, vol. 183, pp. 179-185; U.S.Pat. No. 5,356,630 issued Oct. 18, 1994, U.S. Pat. No. 4,720,384 issuedJan. 19, 1988, U.S. Pat. No. 4,675,381 issued Jun. 23, 1987; UnitedStates Patent Publication 2007/0287800 to Acquarulo published Dec. 13,2007; United States Patent Publication 2005/0238721 published Oct. 27,2005 and United States Patent Publication 2004/0259969 published Dec.23, 2004.

Implantable drug delivery systems possessing electronic conductionproperties such that the implantable device may actuate a target tissueor sense a parameter associated with the target tissue are described inUnited States Patent Publication 2011/0230747 published Sep. 22, 2011Rogers et al., entitled “Implantable Biomedical Devices On BioresorbableSubstrates” and U.S. Provisional Patent application 61/065,8743, filedJun. 12, 2012.

For example, a non-conductive material, such as a polymer may betransformed into an electronically conducting material by introducing anelectrically conductive material into the nano-flow die processing thepolymer. Making an electrically conductive product comprises filling thepolymer with one or more metals or other conducting materials. The term“filling” is generally used to define a state where there are sufficientconductive particles within the product to establish a conductive state.As will generally be understood in the art, this can include a productlayer that only partially comprises conductive elements or particles.Any suitable material that enables or provides for electricalconductivity can be used to create an electrically conductive productusing the polymer, including metals. Circuits prepared by such methodscan be controlled externally or can respond autonomously to endogenoussignals within the patient such as neurotransmission including epilepsy,psychosis, or cardiac dysfunction.

Geometries

The flow streams optionally containing drug substance can be morphedinto laminated ribbons retaining a layered structure corresponding tothe number of laminations from gradually thinner laminations formedwithin the extrusion flow, thereby obtaining smaller and smaller grainfeatures and eventually obtaining nano-sized features. These flows maypossess distinct boundary features.

FIG. 1 illustrates a cross section of one embodiment of an annular layerdrug substance made using the nanolayer die.

The nano die may also be used to create products which will have anincreased interfacial surface area (see FIGS. 2-5). Sections of thelayers mentioned above may be separated by ‘stems’ comprised of a singlematerial or mixture. Each stem may be made of its own respectivematerial or mixture allowing for the properties desired in that stem. Alayer, stem or combination of the two may then be removed by someprocess, whether it is mechanical in nature such as peeling or chemicalin nature such as dissolving. If one of the materials or mixtures usedin the stem along with one or more of the materials used in the layersmay all be removed, the result would be a core with stems protrudingfrom the surface. These stems would have branches (layers) attached witha large surface area exposed to the environment. In the figure above,there are alternating layers of grey and black material separated byalternating grey and black stems. Only six layers are shown in each‘stream’ for illustrative purposes but may comprise of thousands oflayers. If all the black material were removed, the result would be agrey core with four stems each with six branches of material. Thisgreatly increases the surface area exposed to the environment. Bytailoring the rate at which the different materials dissolve along withthe geometry, one could control the release rate of a drug substance bycontrolling the amount of surface area exposed to the environment. Ifthe stems were to dissolve faster, a drug substance that broke up intosections could also be made.

In FIG. 3, the stems are tapered radially inwards. The stems may also bemade to be tapered radially outwards. The stems and branches may all bemade to have different thicknesses and there may be any number of each.

In FIG. 4, above, the core is comprised of a tube made of the greymaterial. Examples of a core include a solid rod, a hollow tube, a wire,or a profile all of which may either be coextruded or extruded onto andmay be comprised of any materials with or without layers. The core mayalso be absent. An outer and/or inner layer may also be added and may becomposed of multiple layers and may be comprised of any suitablematerial or materials.

Multiple layers of streams and stems may also be used to be able tocreate geometries like the one pictured in FIG. 5. Theses layers maycontain different numbers of layers, streams and stems in differentorientations.

Folding in a Coextrusion Die

Time released drug substances may also be made through a typicalcoextrusion head but with layers manipulated through folding to createadditional layers. Such technology is described in Patent Publication2012/0189789 entitled “Method and Apparatus Forming High StrengthProducts” and U.S. Pat. No. 7,690,908 issued Apr. 6, 2010.

This approach to creating multilayered products begins with a typicalflow channel for a product, as is illustrated in FIG. 6 (in the exampleof FIG. 6 the cross-section of this flow channel is an annular ring).The flow channel is then morphed to create folds in the flow channel(steps 1 to 3). These folds are oriented and propagated in such a way sothat the flow may be converged back to a flow passage with a typicalcross section but now with a multiplied number of layers (step 3 to 4).One advantage of this method of layer multiplication over others is thatthe layers remain continuous around the product.

Some other examples of how the folds may be oriented are illustrated inFIG. 7.

The initial flow may contain any number of suitable materials in anynumber of layers and the layer multiplication process may be performedmultiple times. The number of folds and the relative length that theystretch may also vary.

These layer geometries formed through this method allow for a way ofcontrolling the time release of a drug substance much like the nano die.

Stent

This aforesaid layer folding technique may also be used to create anexpanding product such as a stent. A natural weakness at the interfaceof the folds or skin layer may be designed into a stem such that thestem can separate from the underlying support which may be dissolvedeither ex vivo or in vitro. The product so formed could break orseperate at this interface and expand into a larger shape. Thisexpanding product could contain a drug substance and be used in suchapplications as a drug substance releasing stent.

Implantable

Steams including geometric FIGS. 3 and 4 may be extruded as a hollowcore or as an exudate surrounding a preformed pharmaceutical product.Such post flow extrusion work up is known to those in the art.

The invention claimed is:
 1. An extrusion process for preparing amedical device comprising the steps of: combining at least two flowstreams of polymer; subjecting the combined flow streams to repeateddivision and overlapping to amplify the number of laminations whereinthe laminations have micro or nanometer thickness; rejoining theamplified laminations to form a continuous cumulated laminated dieextruded multilayered polymer solid of one or more annular rings,wherein said continuous cumulated laminated die extruded multilayeredpolymer solid is further processed into a medical device which is animplantable device.
 2. The process of claim 1 wherein the medical deviceis a tubular medical device.
 3. The process of claim 2 wherein thetubular medical device is a stent.
 4. The process of claim 1 wherein themedical device further includes a drug substance core wherein said oneor more of said annular rings emanated from the drug substance core. 5.The process of claim 4 wherein the drug substance in the implantabledevice is time-released.
 6. The process according to claim 1 whereinsaid rejoined amplified laminations form a continuous cumulatedlaminated die extruded multilayered polymer solid of annular ringsadditionally comprising induced confined polymer crystallization barrierbetween layers.
 7. The process according to claim 1 wherein saidrejoined amplified laminations form a continuous cumulated laminated dieextruded multilayered polymer solid of annular rings in which the layersare concurrently co-extruded and additionally comprise induced confinedpolymer crystallization barrier between layers.
 8. The process accordingto claim 1, further including forming said one or more of said annularrings into folds or skin layers.
 9. The process according to claim 1,wherein said medical device includes a multi-component polymeric tubecontaining an embedded or extruded annular stem of a first polymer and asupport surface surrounding said embedded or extruded annular stem. 10.The process of claim 2 wherein the tubular medical device is a catheter.11. The process of claim 1 wherein one or more of said annular ringscontains a drug substance.